GB2211186A - Chemical compounds - Google Patents
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- GB2211186A GB2211186A GB8824492A GB8824492A GB2211186A GB 2211186 A GB2211186 A GB 2211186A GB 8824492 A GB8824492 A GB 8824492A GB 8824492 A GB8824492 A GB 8824492A GB 2211186 A GB2211186 A GB 2211186A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Abstract
Compounds of formula:
<IMAGE>
in which R1 denotes either the group (A):
<IMAGE>
in which R4 and R5 are hydrogen or C1-5 alkyl, R6 is hydrogen, C1-5 alkyl, phenyl, halogen, C2-5 alkoxycarbonyl, cyano, amido, mono- or dialkylamido, or the group (B):
<IMAGE>
in which R7 and R8 are hydrogen, C1-5 alkyl, R2 and R3 denote:
<IMAGE>
in which m is 1, 2 or 3, X1 and X2 are hydrogen, alkyl, alkenyl, C5 alkoxy, aralkoxy, aryloxy, halogen, nitrile or azido or X1 and X2 together form a methylenedioxy radical, and their salts, their preparation, their application as medications and new intermediates.
Description
2211186 1-OX-51-988 Chemical Compounds This invention relates to
imidazo[2,1-b]benzothiazoles and acid addition salts thereof, to processes for their preparation, to pharmaceutical compositions containing them and to their use as medicaments.
According to one aspect of the invention there are provided compounds of formula I 0 R2:l N R 3 S [wherein R 1 represents a group of formula II R 4 R 5 R 6 (in which R 4 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; R 5 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; and R 6 represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a phenyl group, a halogen atom, an alkoxycarbonyl group containing 2 to 5 carbon atoms, a cyano group, an amido group or a mono- or dialkylamido group in which each alkyl group contains 1 to 5 carbon atoms), or RI represents a group of formula III 2 R 7 8 (in which R 7 and R8, which may be identical or different, each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms); and R 2 and R 3 together represent a group / C'42 xl (c or 2 (in which m represents an integer from 1 to 3; and X 1 and X2. which may be identical or different, each represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a straight or branchedchain alkenyl group containing 2 to 5 carbon atoms, a straight or branched-chain alkoxy group containing 1 to 5 carbon atoms, an arylalkoxy group, an aryloxy group, a halogen atom or a nitrile or azido group, or X 1 and X 2 together represent a methylenedioxy group)] and acid addition salts thereof. 20 The term 11alkyl group containing 1 to 5 carbon atoms" as used herein includes, for example, straightchain alkyl groups such as methyl, ethyl, proDvl, butyl and pentyl groups and branched alkyl groups such as isopropyl, isobutyl and t-butyl groups. 25 The term nhalogen atomn as used herein preferably refers to a fluorine, chlorine or bromine atom. The term 11alkoxycarbonyl group containing 2 to 5 carbon atoms" as used herein includes, for example, a methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl group.
The term "mono- or dialkylamido group wherein each alkyl group contains 1 to 5 carbon atoms" as used herein includes, for example, a monomethylamido, dimethylamido, monoethylamido, diethylamido, monopropyl5 amido or dipropylamido group.
The term "alkenyl group containing 2 to 5 carbon atoms" as used herein includes, for example, a vinyl, allyl, but-3-enyl or isopropenyl group.
The term "alkoxy group containing 1 to 5 carbon atoms" as used herein includes, for example, a methoxv, ethoxy, propoxy or isopropoxy group.
The term. "arylalkoxy grour)" as used herein includes, for example, a benzyloxy, phenylethoxy or thienylmethoxy group.
The term Ilaryloxy group" as used herein includes, for examole, a phenoxy or naphthyloxy group.
The acid addition salts mav be those of inorganic or organic acids and may be, for example, salts formed with hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, propionic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glvoxylic or aspartic acids, or alkanesulphonic acids such as methanesulphonic acid or arylsulphonic acids such as benzenesulT.)honic acid. 25 Preferred compounds according to the invention are compounds of formula 1 as defined above and acid addition salts thereof wherein R 1 represents a group of formula II in which R 4, R. and R 6 each represents a hydrogen atom or R 1 represents a group of formula III in which R 7 and R 8 each represents a hydrogen atom; and R 2 and R 3 together represent a group xl c or 2 in which Xl and X 2' which may be identical or different, each represents a hydrogen atom, a methyl group, a methoxy group, an isopropoxy group or a benzyloxy group.
Particularly preferred compounds according to the invention are compounds of formula I as defined above and acid addition salts thereof, wherein R 1 represents a group of formula II in which R 41 R. and R6 each represents a hydrogen atom; and R 2 and R3 together represent a group X or X2 in which X 1 represents a hydrogen atom, and X 2 reDresents a methoxy grouD, an isopropoxy group or a benzvloxy group.
Of particular note are the following compounds:
(7-isoproDoxv-imidazo[2,1-b]benzothiazol-2-yl) cyclopropylmethanone; (7methoxy-imidazo[2,1-b]benzothiazol-2-yl) cyclopropylmethanone; (7benzyloxy-imidazo[2,1-b]benzothiazol-2-yl) cyclopropyl-methanone; and (5,6,7,8-tetrahydro-imidazo[2,1-b]benzothiazol- 2yl) cyclopropyl-methanone; and acid addition salts thereof.
The compounds according to the invention may, for example, be prepared according to the following processes, which- processes constitute further features of the pre sent invention:
- 5 A. Compounds of formula I A R2 R 3 ls; A (wherein R 2 and R 3 are as defined above and R' 1 represents a group of formula II in which R4 represents a hydrogen atom and R 5 and R 6 each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms or 'R' 1 represents a group of formula III in which R 7 and R 8 are as defined above) may, for example, be prepared by oxidation of a compound 10 of formula IV R 2 3 (wherein R'l. R2 and R 3 are as defined above).
The oxidation of the compound of formula IV is preferably effected with manganese dioxide, 15 nitric acid, ferric chloride or chromium oxide in the presence of pyridine, or by Oppenauer oxidation or by dehydrogenation in the presence of a copper catalyst.
The compounds of formula IV may conveniently 20 be prepared by reacting a compound of formula v 1 --z R CHO R 3 1J'I r 6 (wherein R 2 and R 3 are as defined above) with a compound of formula VI M-R' (VI) [wherein M represents an alkali metal atom (e.g.
a lithium atom) or a group -Mg-Hal (in which Hal represents a chlorine, bromine or iodine atom) and RY is as defined above].
1 The reaction of the compound of formula V with the compound of formula VI is preferably effected under anhydrous conditions, in an organic solvent such as tetrahydrofuran.
The compounds of formula V may conveniently be prepared by oxidation of a compound of formula VII R OH R 2 S,N 3 (wherein R 2 and R 3 are as defined above).
The oxidation of the compound of formula VII may advantageously be effected by means of manganese dioxide.
The compounds of formula VII may conveniently be prepared by:
(i) Reaction of a compound of formula VIII 2 ---N \--- NH R 3 (VIII) (wherein R 2 and R 3 are as defined above) with 3- 7 bromo-l-hydroxypropan-2-one; or (ii) Reduction of a compound of formula IX C- oo R 2: ú1 S (IX) 3 (wherein R 2 and R 3 are as defined above and R represents 5 an alkyl group containing 1 to 3 carbon atoms).
The reduction is conveniently effected by means of lithium borohydride.
The 2-aminobenzothiazoles of formula VIII may be prepared as described in J. Het. Chem. (1980), 17, 1325 and the 2-amino-4,5,6,7-tetrahydrobenzothiazoles of formula VIII may be prepared as described in J. Gen. Chem. USSR 16, 1701-5 (1946).
The compounds of formula IX may be prepared as described in Farmaco ed. Sci. (1977), 32, 735.
B. Compounds of formula I B R6 (wherein R 2r R 3 r R 4 and R. are as defined above and R' 6 represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a Dhenyl grout), a halogen atom or an alkoxycarbonyl group containing 2 to 5 carbon atoms) may, for example, be prepared by reacting a compound of formula X 8 R 2 N R4 (X) R 3 31 -- -W d \R, (wherein R 2, R 3r R 4 and R 5 are as defined above) with an appropriate cyclising reagent. 5 It will be understood that the cyclising reagent will be a reagent serving to introduce a group CHRI 6 across the vinylic double bond. When a compound of formula I B wherein R 4 represents an alkyl group containing 1 to 5 carbon atoms and R 5 represents a hydrogen atom and R' 6 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms is desired, the cyclisation is advantageously effected by means of trialkylsulphoxonium iodide in the presence of an organic solvent such as dimethylformamide.
When a compound of formula 1 B wherein R 4 represents a hydrogen atom and R 5 represents an alkyl group containing 1 to 5 carbon atoms and R9 6 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms is desired, the cyclisation is advantageously effected by means of dimethylaminoalkylphenyloxosulphonium tetrafluoroborate in the presence of an organic solvent such as dimethyl formamide.
When a compound of formula I B wherein R 4 and R 5 each represents a hydrogen atom and R' 6 represents an alkoxycarbonyl group or a phenyl group is desired, the cyclisation is advantageously effected by means of a dimethylsulphuranylidene alkyl acetate or benzyl dimethyl sulphonium anion in the presence of an organic solvent such as chloroform.
When a compound of formula I B wherein R 4 and 9 R 5 each represents a hydrogen atom and R' 6 represents a halogen atom is desired, the cyclisation is advantageously effected by means of a dimethylaminophenyloxosulphonium halogenomethyl ylide in the presence of an organic 5 solvent such as dimethylformamide.
The compounds of formula X may, for example, be prepared by oxidising a compound of formula XI OH R2 -,,N, / R 'I H \R 3 5 (wherein R 20' R 3 R 4 and R 5 are as defined above).
Oxidation of the compound of formula XI is preferably effected wLth manganese dioxide, nitric acid, ferric chloride or chromium oxide, in the presence of pyridine, or by Oppenauer oxidation or by dehydroqenation in the presence of a copper catalyst.
The compounds of formula XI may, for example, be prepared by reactinq a compound of formula V R ---z CHO 2 N/\T _ 3 cj -- (V) (wherein R 2 and R 3 are as defined above).with a compound of formula XII R 4 1 C = CH - R 5 (M) - [wherein M represents an alkali metal atom (e.g. a lithium atom) or a group -Mg-Hal (in which Hal represents a chlorine, bromine or iodine atom) and R 4 and R 5 are as defined above].
The reaction of the compound of formula V with the compound of formula XII is preferably effected under anhydrous conditions and in an organic solvent such as tetrahydrofuran.
C. Compounds of formula I c 0 R4 0- N C) A CL, (wherein R-,, R R and R are as defined above and 3 4 5 Ra and R'a, which may be identical or different, each represents a hydrogen atom or an alkyl groulp containing 1 to 5 carbon atoms) may, for example, 15 be prepared by reacting a compound of formula I D 0 11 c COOH (wherein R2,' R31' R4 and R. are as defined above) with an amine of formula XIII Ra H N (XIII) \Rt-a (wherein Ra and R1a are as defined above).
The reaction of the compound of formula I D with the amine of formula XIII is preferably effected in the presence of an anhydrous organic solvent 5 and in the presence of carbonyldiimidazole.
The compounds of formula I D may, for example, be prepared by saponification of a compound of formula VB 0 RI. N. P, B R-----S R (wherein R 2 R 3P R 4 and R 5 are as defined above and W' 6 represents an alkoxycarbonyl group containing 2 to 5 carbon atoms).
The saponification of the compound of formula it B is preferably effected by means of an alkali metal hydroxide such as sodium hydroxide.- D. Compounds of formula I E 0 RS (I E) (wherein R 28' R 3, R 4 and R 5 are as defined above) may, for example, be prepared by dehydrating a compound of formula 11 c 0 P'4 N (it c o - NHI. R3 (wherein R 21 R3, R 4 and R. are as defined above).
The dehydration of the compound of formula VC is preferably effected by means of the anhydride of a strong acid such as trifluoroacetic acid anhydride in the presence of an organic solvent such as dichloromethane.
The compounds of formula I are basic in character and may therefore, if desired, be subsequently converted into their acid addition salts.
Advantageously, the acid addition salts of the compounds of formula I may be prepared by reacting, in approximately stoichiometric proportions, an inorganic or organic acid with the compound of formula I. The salts may be prepared without intermediate isnlation of the corresponding base.
The compounds according to the invention -possess very interesting pharmacological properties; of Particular note are their weak to strong benzodiazepine inverse agonist properties, depending on their substitution pattern. In addition, some of the compounds also possess tranquillising properties. These properties are further illustrated in the exoerimental section.
The compounds according to the invention are thus of use as medicaments. Therefore, according to a further aspect of the invention there is provided the use of compounds of formula 1 as defined above and pharmaceutically acceptable acid addition salts thereof as medicaments.
Compounds according to the invention preferred for use as medicaments are those wherein, in formula I, R 1 represents a group of formula II in which R4 R 5 and R 6 each represents a hydrogen atom or R 1 represents a group of formula III in which R 7 and 8 each represents a hydrogen atom; and R2 and 3 together represent a group X or X 2 wherein X 1 and X21 which may be identical or different, each represents a hydrogen atom, a methyl group, a methoxy group, an isopropoxy group or a benzyloxy group; and pharmaceutically acceptable acid addition salts thereof.
Compounds according to the invention particularly preferred for use as medicaments are those wherein, in formula I, R 1 represents a group of formula II and R, each represents a hydrogen in which R 4F R 5 atom; and R 2 and R 3 together represent a group X or wherein X 1 represents a hydrogen atom and X2 represents a methoxy group, an isopropoxy group or a benzyloxy group; and pharmaceutically acceptable acid addition salts thereof.
Of particular note are the following compounds according to the invention, for use as medicaments: (7-isopropoxy-imidazo[2,1-b]benzothiazol-2-yl) cyclopropyl methanone; (7-methoxy-imidazo[2,1-b]benzothiazol-2-yl) cyclopropylmethanone; (7-benzyloxy-imidazo[2,1-b]benzothiazol-2-yl) cyclopropylmethanone; and (5,6,7,8-tetrahydro-imidazo[2,1-b]benzothi-azol2-yl) cyclopropyl-methanone; and pharmaceutically acceptable acid addition salts thereof..
These medicaments may be used, for example, in the treatment of memory disorders, particularly in geriatrics, and in cerebral senescence disorders. Some compounds may also be used in the treatment of obesity and as minor tranquillisers in the treatment of certain agitated or irritable conditions.
The normal dose, which varies according to the compound used, the patient treated and the condition concerned may, for example, be from 0.1 mg to 200 mg per day by the oral route.
According to a further aspect of the invention there are provided pharmaceutical compositions containing, as active ingredient, at least one compound of formula 1 as defined above or a pharmaceutically acceptable acid addition salt thereof.
As medicaments, the compounds of formula 1 and pharmaceutically acceptable acid addition salts thereof may be incorporated into pharmaceutical compositions for the digestive or parenteral route.
These pharmaceutical compositions may be, for example, solid or liquid and may be in conventional pharmaceutical forms used in human medicine, for example plain or coated tablets, capsules including qelatin capsules, granules, suppositories, solutions e.g. for injection; these may be prepared according to conventional methods. The active ingredient(s) may be used in conjunction with excipients customarily employed in pharmaceutical compositions, such as talc, gum arabic, lactose, starch, maqnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents or preservatives.
The following intermediates useful in the preparation of the compounds of formula I are themselves new and comprise a further aspect of the invention:
- the compounds of formula IV c) H R 2, (M R 3 (wherein R' 1J. R 2 and R 3 are as defined above); - the compounds of formula XI OH _-K4 R 2r (M) R 3 R 5 (wherein R2, R 3, R 4 and R. are as defined above); - the compounds of formula X 0 R 2 N R4 (X) R 3 S/- H (wherein R2 p R 3 r R4 and R. are as defined above); and - the compounds of formula I D 0 11 R4 c --- R D COOH (wherein R 2, R 3 R 4 and R 5 are as defined above).
The following non-limiting Examples illustrate the invention in greater detail:
16 - Preparation A: 7-methoxy-imidazo[2,1-b3benzothiazole-2-carboxaldehyde a).7-Methoxy-imidazo[2,1-b]benzothiazole-2-methanol 5 2-Amino-5-methoxybenzothiazole (11.6 g, 0.069 mole) and 3-bromo-lhydroxypropan-2-one (11.6 g, 0.076 mole) in dry T.H.P. (1O ml) were stirred under nitrogen at 80 for 3 hrs. The mixture was cooled in ice and the supernatant liquid decanted. The residue was heated in ethanol (60 ml) for 1 hr, cooled and filtered to give-7-methoxy-imidazo[2, 1-b]benzothiazole2-methanol hydrobromide as a pale yellow solid. The product was dissolved in water, basified with aqueous sodium bicarbonate and extracted into chloroform (5 x 200 ml). The extracts were dried over magnesium sulphate, concentrated under reduced pressure and diluted with diethyl ether to give 7-methoxy-imidazo[2,1- b]benzothiazole-2-methanol as colourless crystals (6.30 g, 42%) mpt 202-5 (EtOH). Found: 56.32% C,.4.36% H, 11.93% N, 13.69% S; calc. C 11 H 10 N 2 0 2 S, 56.40% C, 4.30% H, 11.96% N, 13.68% S.
b) 7-Methoxy-imidazo[2,1-bjbenzothiazole-2- carboxaldehyde 7-Methoxy-imidazo[2,1-b]benzothiazole-2-methanol (5.0 9, 0.0225 mole) and manganese dioxide (10 g, 0.115 mole) were stirred under reflux in chloroform (500 ml) for 2 hrs. The mixture was filtered hot through celite and evaporated under reduced pressure to give 7-methoxyimidazo[2,1-blbenzothiazole-2- carboxaldehyde (3.92 9, 79%) as colourless crystals mpt 214-50 (EtOH). Found: 56.79% C, 3.56% H, 12.08%--N, 13.75% S; calc. C 11 H 8 0 2 N 2 S, 56.89% C, 3.47% 9, 12.06% N,- 13.80% S.
17 - Example 1: -(7-Methoxy-imidazo[2,1-blbenzothiazol2-yl) cyclopropyl methanone Step A: (7-Methoxy-imidazo[2,1-blbenzothiazol5 2-yl) cyclopropyl methanol Cyclopropyl magnesium bromide. prepared from cyclopropyl bromide (3.6 g, 0.03 mole) and magnesium (0.8 g, 0.033 mole) in dry T.H.F. (50 ml), was added dropwise to a suspension of 7-methoxyimidazo[2,1bjbenzothiazole-2-carboxaldehyde (3.9 g, 0.0177 mole) in dry T.H.F. (80 ml). The mixture was stirred at R.T. for 3 hrs and quenched with saturated aqueous ammonium chloride solution.
The mixture was extracted with ethyl acetate and the extracts dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with 2% methanol/dichloromethane to give (7-metboxy- imidazo[2,1-b]benzothiazol-2-yl) cyclopropyl methanol (2.75 g, 69%) as a colourless solid mpt 151-3 (EtOH). Found: 61.17% C, 5.23% H, 10.24% N, 11. 48% S; calc. C 14 lq 14 N 2 0 2 S, 61.30% C, 5.14% H, 10.21% N, 11.69% S.
Step B: (7-Methoxy-imidazo[2,1-b]benzothiazol-2- yl) cyclopropyl methanone 1 (7-Methoxy-imidazo[2,1-b]benzothiazol-2-yl) cyclopropyl methanol (1.63 g, 0.0062 mole) and manganese dioxide (4.8 g, 0.055 mole) were stirred under reflux in chloroform (300 ml) for 1 hr. The mixture was filtered hot and evaporated to dryness. Trituration with diethyl ether gave (7-methoxy-imidazo[2,1-b]benzothiazol- 2-yl) cyclopropyl methanone as a colourless solid (1.45 g, 89%) mpt 213- 40 (EtOH). Found: 62.01% C, 4.49% H, 10.32% N, 11.76% S; calc. C14 H 12 N 2 0 2 S, 61.75% C, 4.44% H, 10.29% N, 11.77% S.
Examples 2 to 8 Using the method of Example 1, but starting from the corresponding compounds of formula V in which R 2 and R 3 have the meanings indicated in Table I, the compounds of Examples 2 to 8 were prepared.
Yield, melting point, IR Spectrum and analytical data are given in Table I.
X Table
Exam- Yield R 1 R 2 R 3 mpt I.R cm-1 Analysis H N 7r 571 ple 89 213-40 3150 (C 1 H), 1649 (C=O), 1618, Found 62.01 4.49 10.32 11.76 1518, 1507p 1488, 1377 C14H12N2 0 2 S 61.75 4.44 10.29 11.77 2 92 204-50 3160 (C 1 H), 1650 (C=O), 1518 Found 64.18 4.22 11.51 13.25 1502$ 1374, 1209, 1050 c 13 H 10 N 2 OS 64.44 4.16 11.56 13.23 3 85 235-60 3140 (C 1 H), 1651 (C=O), 1587, Found 61.48 4.51 10.22 11.67 1524br, 1423, 13749 1286 C14 H 12 N 2 0 2 s 61.76 4.44 10.29 11.77 4 91 Raj 195-70 3160 (C 1 H), 1651 (C=O), 1519, Found 68.70 4.70 8.01 9. 15 C:1 1501p 14813 1280, 1197 c 20 H 16 N 2 0 2 s 68.95 4.63 8.04 9.20 h -i ko Table 1 (Continued) Exam- Yield R 1 R 2 R 3 mpt I.R cm-1 Analysis -5 ple 75 -<1 304-70d 3140 (C 1 H), 1655 (C=O), 1520, Found 1500) l466 1381, 1254 C14H1ON 2 03 S 58.73 3.52 9.78 11.2C 6 -41 182-40 3100 (C 1 H), 1650 (C-0), 1512, Found 63.52' 5.78 11.59 12. 95 1443) 1378, 1311, 1234 c 13 H 14 N 2 os 63.39 5.73 11.73 13.02 Pr 7 85 1.48-500 3120 (c 1 H), 1650 W=O), 1610, 1.516, Found 63.82 5.45 9.24 10.71 1497, 1475, 1370, 1290 c 16 H 16 N 2 0 2 S 63.98 5.37 9.33 10.67 8 81 Mlle),:,,, 286-80 3120 (C H), 1639(C--0), 1500, 1362, Found 66.47 5. 291.0.30 11.89 1 1295, 1187, 1160 c H N OS 66.64 5.22 10.36 11.86 14 2 A 21 - The 6-methoxy-imidazo[2,1-b]benzothiazole-2-methanol used as starting material of Example 3 (compound of formula VII) was prepared as indicated below.
Preparation B: 6-Methoxy-imidazo[2,1-b]benzothiazole-2methanol Ethyl imidazo[2,1-b]benzothiazole-2-carboxylate (4.0 9) in dry T.H.F. was stirred with lithium borohydride (1.5 g) for 48 hrs at room temperature under dry nitrogen. The mixture was treated with an excess of 2N hydrochloric acid and warmed to 50 for 2 hrs to decompose the comnlex. The mixture was basified with aqueous sodium bicarbonate and extracted into ethyl acetate. The extracts were dried over magnesium sulphate and evaporated to drvness under reduced Pressure to give 6-metnoxyimidazo[2,1-b]benzothiazole-2- methanol as a colourless solid (3.27 g, 96.4%), mpt 189-900 (Eton-). Found: 56.37% C, 4.38% H, 11.90% N, 13.65% S; calc. C 11 H 10 N202s, 56.40% C, 4.30% H, 11.96% N, 13.69% S.
Example 9
Tablets were prepared according to the following formulation:
Compound of Example 1 20 mg Excipient for one tablet up to 150 mq (details of the excipient: lactose, starch, talc, magnesium stearate).
Example 10
Tablets were prepared according to the following formulation:
Compound of Example 4 20 mg - Excipient for one tablet up to 150 mg (details of the excipient: lactose, starch, talc, magnesium stearate).
Biochemical Activity The affinity of the active ingredients for the benzodiazepine receptors was measured using a radioactively labelled ( 3 H) compound flunitrazepam, and a modified version of the method of Squires and Braestrup (Nature, 1977, 266, 732).
The values given in Table 2 below are the concen- tration (mol x 10-9) of the compound under test which inhibits 50% of the specific binding of 0.6 x 10- 9 mol of 3 H-labelled flunitrazepam in preparations of membranes from the rear portion of the brain in rats (IC so values).
Table 2
EXAMPLE Binding to Receptors IC so n14 1 2.5 2 20 3 1000 4 3.2 158 6 79 7 6.3 8 60 23 lox 5-1 -988 Compounds of formula I R N R 2 S)--N 3 [wherein R 1 represents a group of formula II R 4 R 5 R 6 (in which R 4 reDresents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; R. represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; and R 6 represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a phenyl group, a halogen atom, an alkoxycarbonyl group containing 2 to 5 carbon atoms, a cyano group, an amido group or a monoor dialkylamido group in which each alkyl group contains 1 to 5 carbon atoms), or R 1 represents a group of formula III 7 (in which R 7 and R.. which may be identical or different, 24 - each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms); and R2 and R3 together represent a group CH2 or 2 CJ42 (in m represents an integer from 1 to 3; and Xl and X21 which mav be identical or different, each represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a straight or branched-chain alkenyl group containing 2 to 5 carbon atoms, a straight or branched-chain alkoxy group containing 1 to 5 carbon atoms, an arylalkoxy group, an aryloxy group, a halogen atom or a nitrile or azido group, or X 1 and X2 together represent a methylenedioxy group)] and acid addition salts thereof. 2. Compounds as claimed in claim 1 wherein R 1 represents a group of formula II in which R4P R5 and R6 each represents a hydrogen atom or Ri represents a group of formula III in which R7 and R8 each represents a hydrogen atom; and R., and R together represent a group 3 xl or X2 in which Xl and X2. which may be identical or different, each represents a hydrogen atom, a methyl group, a methoxy group, an isopropoxy group or a benzyloxy group. 3. Compounds as claimed in claim 1 or claim 2 wherein R 1 represents a group of formula II in which R 4, R 5 and R 6 each represents a hydrogen atom; and R 2 and R 3 together represent a group or X 2 in which X 1 represents a hydrogen atomr and X.) represents a methoxy group, an isopropoxy group or a benzvloxy group.
4. (7-Isopropoxy-imidazo[2,1-b]benzothiazol-2-vl) cyclo-orolovl-methanone; (7-methoxy-imidazo[2,1-b]benzothiazol-2-yl) cyclopropyl methanone; (7-benzyloxv-imidazo[2,1-b]benzothiazol-2-yl) cyclopropyl methanone; and (5,6,7,8-tetrahydro-imidazo[2,1-b]benzothiazol-2-yl) cyclopropyl-methanone; and acid addition salts thereof.
5. Physiologically acceptable acid addition salts of comDounds of formula 1 as defined in claim 1.
6. ComPounds as claimed in claim 1 as herein specif- ically disclosed in any one of Examples 1 to 8. 7. A process for the preparation of a compound of formula I A R2 R 3 (wherein R 2 and 'R 3 are as defined in claim 1 and R' 1 represents a group of formula II as defined in claim 1 in which P, 4 represents a hydrogen atom and R 5 and R 6 each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms or R' 1 represents a group of formula III as defined in claim 1 in which R 7 and R 8 are as defined in claim 1) which comprises oxidation of a compound of formula IV OH R (M 2 R 3 (wherein W1. R 2 and R 3 are as defined above).
8. A process as claimed in claim 7 wherein the oxidation of the compound of formula IV is effected with manganese dioxide, nitric acid, ferric chloride or chromium oxide in the presence of pyridine, or by Oppenauer oxidation or by dehydrogenation in the presence of a copper catalyst.
9. A process as claimed in claim 7 or claim 8 wherein the com.Dound of formula IV is prepared by reacting a compound of formula V R CHO 2 (V) R 3 (wherein R 2 and R 3 are as defined in claim 1) with a compound of formula VI M-R' 1 (VI) [wherein M represents an alkali metal atom or a group -Mg-Hal (in which Hal represents a chlorine, bromine or iodine atom) and R' 1 is as defined in claim 7].
10. A process as claimed in claim 9 wherein the reaction of the compound of formula v with the compound of formula VI is effected under anhydrous conditions, in an organic solvent such as tetrahydro5 furan. 11. A process as claimed in claim 9 or claim 10 wherein the com-pound of formula V is prepared by oxidation of a compound of formula VII R N OH R 2 S N (VII) 3 (wherein R9 and R 3 are as defined in claim 1). 12. A process as claimed in claim 11 wherein the oxidation of the comPound of formula 'VII is effected by means of manganese dioxide. 13. A process as claimed in claim 11 or claim 12 wherein the comnound of formula VII is 1DrePared by reacting a compound of formula VIII R2 ---N R N H 2 (VIII) (wherein R. and R 3 are as defined in claim 1) with 3-bromo-l-hydroxvpropan-2-one, 14. A process as claimed in claim 11 or claim 12 wherein the compound of formula VII is prepared by reducing a compound of formula IX C- 00 R 2 114 1 >.,N (M R 3 IúS (wherein R 2 and R 3 are as defined in claim 1 and R represents an alkyl group containing 1 to 3 carbon atoms). 15. A process as claimed in claim 14 wherein the reduction is effected bv means oflithium boro- hydride. 16. A Process for the preparation of a compound of is Rz; B) W6 (wherein R 27 'R 3r R 4 and R 5 are as defined in claim 1 and R' represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a phenyl group, a halogen atom or an alkoxycarbonyl group containing 2 to 5 carbon atoms) which comprises reacting a compound of formula X 0 R N R4 R 3 (wherein R 2 F R 3r R4 and R. are as defined in claim 1) with an appropriate cyc'lising reagent.
17. A process as claimed in claim 16 wherein in the desired compou"nd of formula I.r P4 represents an alkyl group containing 1 to 5 carbon atoms and R 5 represents a hydrogen atom and R16 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms and the cyclisation is effected by means of trialkylsulphoxonium iodide in the presence of an organic solvent such as dimethylformamide. 18. A process as claimed in claim 16 wherein in the desired compound of formula I BP R 4 represnts a hydrogen atom and R 5 represents an alkyl qroup containing 1 to 5 carbon atoms and R' 6 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms and the cyclisation is effected by means of dimethylaminoalkylohenyloxosulphonium tetrafluoroborate in the presence of an organic solvent such as dimethyl formamide. 19. A process as claimed in claim 16 wherein in the desired compound of formula I,, R 4 and R 5 each represents a hydrogen atom and R' 6 represents an alkoxycarbonyl group or a phenyl group and the cyclisation is effected by means of a dimethylsulphuranvlidene alkyl acetate or benzyl dimethyl sulphonium anion in the presence of an organic solvent such as chloroform. 20. A process as claimed in claim 16 wherein in the desired compound of formula I,, R 4 and R 5 each represents a hydrogen atom and R'6 represents a halogen atom and the cyclisation is effected by means of a dimethylaminophenyloxosulphonium halogenomethyl ylide in the presence of an organic solvent such as dimethylformamide.
21. A process as claimed in any one of claims 16 to 20 wherein the compound of formula X is prepared by oxidising a compound of formula XI OH R2 14 (XI) R -11 S R 3 5 (wherein R 2, R3, R4 and R. are as defined in claim 1). 22. A process as claimed in claim 21 wherein the oxidation is effected with manganese dioxide, nitric acid, ferric chloride or chromium oxide, in the presence of pyridine, or by Oppenauer oxidation or by dehydrogenation in the presence of a copper catalyst. 23. A process as claimed in claim 21 or claim 22 wherein the compound of formula XI is prepared by reacting a compound of formula V R CHO 2::
is R 3 (V) (wherein R 2 and R 3 are as defined in claim 1) with a comoound of formula XII R.
1 4 C = CH - R 5 (M) [wherein M represents an alkali metal atom or a group -Mg-Hal (in which Hal represents a chlorine, bromine or iodine atom) and R 4 and R 5 are as defined in claim 1]. 24. A process as claimed in claim 23 wherein the reaction of the compound of formula V with the compound of formula XII is effected under anhydrous conditions and in an organic solvent. 25. A Process for the preparation of a compound of formula I C 0 94 - 31 - CO N J CL, c 3 (wherein R 2 R 3, R 4 and R. are as defined in claim 1 and Ra and R'a, which may be identical or different, each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms) which comprises reacting a compound of formula I D 0 11 R4 N. c D COOH (wherein R 2' 'R3' 'R4 and R 5 are as defined above) with an amine of formula XIII H - N / Ra (XIII) \R'a (wherein Ra and R1a are as defined above). 26. A process as claimed in claim 25 wherein the.reaction of the comnound of formula I D with the amine of formula XIII is effected in the presence of an anhydrous organic solvent and in the presence of carbonyldiimidazole. 27. A process as claimed in claim 26 wherein the compound of formula I D is preDared by saponifi- cation of a compound of formula V B 0 R4 N / P, B) (wherein R 2, R 3, R 4 and R 5 are as defined in claim 1 and W' 6 represents an alkoxycarbonyl group containing 2 to 5 carbon atoms). 28. A process as claimed in claim 27 wherein the saponification of the compound of formula 1' T3 is effected by means of an alkali metal hydroxide. 29. A process for the preparation of a compound of formula I RE 0 R 11 4 fl A2 (wherein R 2, R 3, R 4 and R 5 are as defined in claim 1) which comprises dehydrating a compound of formula it c 0 F, tl. P's (It C-0 - NH2. C) R3 (wherein R- 2, R 3, R 4 and R 5 are as defined above). 30. A process as claimed in claim 29 wherein the dehydration of the compound of formula V c is effected by means of trifluoroacetic acid anhydride in the presence of an organic solvent.
31. A Process as claimed in any one of claims 7 to 30 wherein a compound of formula I initially obtained is subsequently converted into an acid addition salt thereof and/or an acid addition salt of a compound of formula I is subsequently converted into a compound of formula I.
32. A process for the preparation of compounds as claimed in claim 1 substantially as herein described. 33. A process for the preparation of comDounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 8.
34. Compounds of formula I as defined in claim 1 and acid addition salts thereof whenever prepared bv a process as defined in any one of claims 7 to 33. 35. Compounds as claimed in any one of claims 1 to 6 for use in therapy. 36. The use of a compound as claimed in any one of claims 1 to 6 for the manufacture of a medicament for the treatment of memory or cerebral senescence disorders, obesity or agitated or irritable conditions.
37. Pharmaceutical compositions comprising, as active ingredient,.at least one compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof in.association with a pharmaceutical carrier and/or excipient.
38. Compositions as claimed in claim 37 wherein the active ingredient comprises a compound as defined in any one of claims 2 to 6. 39. Compositions as claimed in claim 37 or claim 37 in the form of dosage units.
40. Compositions as claimed in claim 39 wherein each dosage unit contains from 0.1 to 200 mg of active ingredient. 41. Pharmaceutical compositions as claimed in claim 37 substantially as herein described.
42. Pharmaceutical compositions substantially as herein described in Example 9 or 10.
43. Compounds of formula IV as defined in claim 7.
44. Compounds of formula XI as defined in claim 21. 45. Compounds of formula I D as defined in claim 25.
46. Each and every novel method, process, compound and composition herein disclosed.
Published 1989 at The Patent Offtce,Statel-Iouse,66..71 HigliHolborn, LondorWC1R4Tp.purther copies maybe Obtainedfrom The Patent=ceSales Branch, St Mary Cray, Orpington. Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent, Con. 1187
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878724566A GB8724566D0 (en) | 1987-10-20 | 1987-10-20 | Chemical compounds |
Publications (3)
| Publication Number | Publication Date |
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| GB8824492D0 GB8824492D0 (en) | 1988-11-23 |
| GB2211186A true GB2211186A (en) | 1989-06-28 |
| GB2211186B GB2211186B (en) | 1991-07-31 |
Family
ID=10625613
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB878724566A Pending GB8724566D0 (en) | 1987-10-20 | 1987-10-20 | Chemical compounds |
| GB8824492A Expired - Lifetime GB2211186B (en) | 1987-10-20 | 1988-10-19 | Chemical compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB878724566A Pending GB8724566D0 (en) | 1987-10-20 | 1987-10-20 | Chemical compounds |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4895863A (en) |
| EP (1) | EP0313458B1 (en) |
| JP (1) | JPH01193274A (en) |
| AT (1) | ATE92928T1 (en) |
| AU (1) | AU613413B2 (en) |
| CA (1) | CA1331991C (en) |
| DE (1) | DE3883140T2 (en) |
| DK (1) | DK170024B1 (en) |
| ES (1) | ES2059552T3 (en) |
| GB (2) | GB8724566D0 (en) |
| GR (1) | GR3009703T3 (en) |
| HU (1) | HU201769B (en) |
| MX (1) | MX173422B (en) |
| PT (1) | PT88795B (en) |
| RU (1) | RU2014334C1 (en) |
| ZA (1) | ZA887433B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2230779A (en) * | 1989-04-19 | 1990-10-31 | Roussel Lab Ltd | Imidazo [2, 1-b] benzothiazoles |
| GB2232666A (en) * | 1989-04-19 | 1990-12-19 | Roussel Lab Ltd | Imidazo [2,1-b] benzothiazoles |
| US5851425A (en) * | 1996-04-04 | 1998-12-22 | Rolic Ag | Imidazothiazoles |
| WO2015145336A1 (en) | 2014-03-27 | 2015-10-01 | Torrent Pharmaceuticals Limited | Novel fused imidazobenzothiazole compounds |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2679136A1 (en) * | 1991-07-19 | 1993-01-22 | Synthelabo | Medicaments and pharmaceutical compositions based on imidazo[2,1-b]benzothiazol-3-acetamide derivatives |
| FR2679232B1 (en) * | 1991-07-19 | 1994-01-14 | Synthelabo | ALPHA-HYDROXYIMIDAZO [2,1-B] BENZOTHIAZOLE-3-ACETAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| FR2679231B1 (en) * | 1991-07-19 | 1994-01-14 | Synthelabo | IMIDAZO [2,1-B] BENZOTHIAZOLE-3-ACETAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION, IN THERAPEUTICS. |
| FR2679233B1 (en) * | 1991-07-19 | 1993-10-15 | Synthelabo | IMIDAZO [2,1-B] BENZOTHIAZOLE-3-ACETAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| EP0524055A1 (en) * | 1991-07-19 | 1993-01-20 | Synthelabo | Imidazo(2,1-b)benzothiazole-3-acetamide derivatives, process for their preparation and their therapeutical use |
| FR2699920B1 (en) * | 1992-12-24 | 1995-02-10 | Synthelabo | Imidazo [2,1-b] benzothiazole-3-acetamide derivatives, their preparation and their therapeutic use. |
| FR2699921B1 (en) * | 1992-12-30 | 1995-02-10 | Synthelabo | 2- (Thien-2-yl) imidazo [2,1-b] benzothiazole-3-acetic acid derivatives, their preparation and their therapeutic use. |
| DE10004572A1 (en) * | 2000-02-02 | 2001-08-09 | Boehringer Ingelheim Pharma | New positive allosteric AMPA receptor modulators (PAARM), processes for their production and their use as medicines |
| AR039475A1 (en) | 2002-05-01 | 2005-02-23 | Wyeth Corp | 6-ALQUILIDEN-PENEMS TRICICLICOS AS BETA-LACTAMASA INHIBITORS |
| AR039774A1 (en) | 2002-05-01 | 2005-03-02 | Wyeth Corp | 6-BICYCLE RENTAL-PENEMS AS BETA-LACTAMASAS INHIBITORS |
| GT200600380A (en) * | 2005-08-24 | 2007-03-29 | BETA-LACTAMASA INHIBITORS PREPARATION PROCESS |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH621126A5 (en) * | 1974-02-07 | 1981-01-15 | Plantex Ltd | |
| US4464384A (en) * | 1981-12-23 | 1984-08-07 | Yamanouchi Pharmaceutical Co., Ltd. | 2-Phenylimidazo[2,1-b]benzothiazole compounds, salts thereof, process of producing them, and pharmaceutical compositions containing them |
| US4721721A (en) * | 1984-12-18 | 1988-01-26 | Rorer Pharmaceutical Corporation | 6-(4-thiazole) compounds, cardiotonic compositions including the same, and their uses |
| IL78834A (en) * | 1985-05-23 | 1992-07-15 | Smithkline Beckman Corp | 2,3-dihydro-5-(1,4-dihydropyridin-4-yl)-6-phenylimidazo(2,1-b)thiazoles and 6,7-dihydro-3-(1,4-dihydropyridin-4-yl)-2-phenyl-5h-imidazo(2,1-b)(1,3)thiazines and their use as intermediates in a process for preparing the corresponding pyridyl-substituted imidazo(2,1-b)thiazoles and 5h-imidazo(2,1-b)(1,3)thiazines |
| ZW24186A1 (en) * | 1985-12-12 | 1987-07-08 | Smithkline Beckman Corp | Inhibition of the 5-lipoxygenase pathway |
-
1987
- 1987-10-20 GB GB878724566A patent/GB8724566D0/en active Pending
-
1988
- 1988-10-04 ZA ZA887433A patent/ZA887433B/en unknown
- 1988-10-14 JP JP63257426A patent/JPH01193274A/en active Pending
- 1988-10-18 MX MX013455A patent/MX173422B/en unknown
- 1988-10-18 DK DK579688A patent/DK170024B1/en not_active IP Right Cessation
- 1988-10-18 US US07/259,285 patent/US4895863A/en not_active Expired - Fee Related
- 1988-10-19 DE DE88402634T patent/DE3883140T2/en not_active Expired - Fee Related
- 1988-10-19 HU HU885344A patent/HU201769B/en not_active IP Right Cessation
- 1988-10-19 EP EP88402634A patent/EP0313458B1/en not_active Expired - Lifetime
- 1988-10-19 GB GB8824492A patent/GB2211186B/en not_active Expired - Lifetime
- 1988-10-19 ES ES88402634T patent/ES2059552T3/en not_active Expired - Lifetime
- 1988-10-19 AU AU23978/88A patent/AU613413B2/en not_active Ceased
- 1988-10-19 PT PT88795A patent/PT88795B/en not_active IP Right Cessation
- 1988-10-19 AT AT88402634T patent/ATE92928T1/en not_active IP Right Cessation
- 1988-10-19 CA CA000580679A patent/CA1331991C/en not_active Expired - Fee Related
-
1992
- 1992-01-14 RU SU925010659A patent/RU2014334C1/en active
-
1993
- 1993-11-11 GR GR930400671T patent/GR3009703T3/el unknown
Non-Patent Citations (1)
| Title |
|---|
| J. Med. Chem. 31(6) 1220 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2230779A (en) * | 1989-04-19 | 1990-10-31 | Roussel Lab Ltd | Imidazo [2, 1-b] benzothiazoles |
| GB2232666A (en) * | 1989-04-19 | 1990-12-19 | Roussel Lab Ltd | Imidazo [2,1-b] benzothiazoles |
| GB2232666B (en) * | 1989-04-19 | 1992-09-30 | Roussel Lab Ltd | Imidazobenzthiazoles |
| GB2230779B (en) * | 1989-04-19 | 1992-10-07 | Roussel Lab Ltd | Imidazothiazolyl cyclopropyl methanones |
| US5851425A (en) * | 1996-04-04 | 1998-12-22 | Rolic Ag | Imidazothiazoles |
| WO2015145336A1 (en) | 2014-03-27 | 2015-10-01 | Torrent Pharmaceuticals Limited | Novel fused imidazobenzothiazole compounds |
| CN106414458A (en) * | 2014-03-27 | 2017-02-15 | 托伦特药物有限公司 | Novel fused imidazobenzothiazole compounds |
| US9908898B2 (en) | 2014-03-27 | 2018-03-06 | Torrent Pharmaceuticals Limited | Fused imidazobenzothiazole compounds |
| US10227361B2 (en) | 2014-03-27 | 2019-03-12 | Torrent Pharmaceuticals Limited | Fused imidazobenzothiazole compounds |
| CN106414458B (en) * | 2014-03-27 | 2019-10-29 | 托伦特药物有限公司 | Novel fused imidazo benzothiazole compound |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2397888A (en) | 1989-04-20 |
| DE3883140T2 (en) | 1994-01-13 |
| HU201769B (en) | 1990-12-28 |
| MX173422B (en) | 1994-03-03 |
| DK579688A (en) | 1989-04-21 |
| HUT50836A (en) | 1990-03-28 |
| RU2014334C1 (en) | 1994-06-15 |
| DK170024B1 (en) | 1995-05-01 |
| EP0313458B1 (en) | 1993-08-11 |
| PT88795B (en) | 1993-01-29 |
| GB8724566D0 (en) | 1987-11-25 |
| EP0313458A3 (en) | 1990-10-31 |
| MX13455A (en) | 1993-10-01 |
| JPH01193274A (en) | 1989-08-03 |
| AU613413B2 (en) | 1991-08-01 |
| GR3009703T3 (en) | 1994-02-28 |
| GB2211186B (en) | 1991-07-31 |
| US4895863A (en) | 1990-01-23 |
| ZA887433B (en) | 1990-01-31 |
| DK579688D0 (en) | 1988-10-18 |
| GB8824492D0 (en) | 1988-11-23 |
| ATE92928T1 (en) | 1993-08-15 |
| DE3883140D1 (en) | 1993-09-16 |
| ES2059552T3 (en) | 1994-11-16 |
| CA1331991C (en) | 1994-09-13 |
| EP0313458A2 (en) | 1989-04-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19971019 |